Prevalence of dementia in the United States: the aging, demographics, and memory study.

AIM: To estimate the prevalence of Alzheimer's disease (AD) and other dementias in the USA using a nationally representative sample. METHODS: The Aging, Demographics, and Memory Study sample was composed of 856 individuals aged 71 years and older from the nationally representative Health and Retirement Study (HRS) who were evaluated for dementia using a comprehensive in-home assessment. An expert consensus panel used this information to assign a diagnosis of normal cognition, cognitive impairment but not demented, or dementia (and dementia subtype). Using sampling weights derived from the HRS, we estimated the national prevalence of dementia, AD and vascular dementia by age and gender. RESULTS: The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002. The corresponding values for AD were 9.7% and 2.4 million individuals. Dementia prevalence increased with age, from 5.0% of those aged 71-79 years to 37.4% of those aged 90 and older. CONCLUSIONS: Dementia prevalence estimates from this first nationally representative population-based study of dementia in the USA to include subjects from all regions of the country can provide essential information for effective planning for the impending healthcare needs of the large and increasing number of individuals at risk for dementia as our population ages.

National estimates of the quantity and cost of informal caregiving for the elderly with dementia.

OBJECTIVE: Caring for the elderly with dementia imposes a substantial burden on family members and likely accounts for more than half of the total cost of dementia for those living in the community. However, most past estimates of this cost were derived from small, nonrepresentative samples. We sought to obtain nationally representative estimates of the time and associated cost of informal caregiving for the elderly with mild, moderate, and severe dementia. DESIGN: Multivariable regression models using data from the 1993 Asset and Health Dynamics Study, a nationally representative survey of people age 70 years or older (N = 7,443). SETTING: National population-based sample of the community-dwelling elderly. MAIN OUTCOME MEASURES: Incremental weekly hours of informal caregiving and incremental cost of caregiver time for those with mild dementia, moderate dementia, and severe dementia, as compared to elderly individuals with normal cognition. Dementia severity was defined using the Telephone Interview for Cognitive Status. RESULTS: After adjusting for sociodemographics, comorbidities, and potential caregiving network, those with normal cognition received an average of 4.6 hours per week of informal care. Those with mild dementia received an additional 8.5 hours per week of informal care compared to those with normal cognition (P < .001), while those with moderate and severe dementia received an additional 17.4 and 41.5 hours (P < .001), respectively. The associated additional yearly cost of informal care per case was 3,630 dollars for mild dementia, 7,420 dollars for moderate dementia, and 17,700 dollars for severe dementia. This represents a national annual cost of more than 18 billion dollars. CONCLUSION: The quantity and associated economic cost of informal caregiving for the elderly with dementia are substantial and increase sharply as cognitive impairment worsens. Physicians caring for elderly individuals with dementia should be mindful of the importance of informal care for the well-being of their patients, as well as the potential for significant burden on those (often elderly) individuals providing the care.

Acute but not chronic caffeine impairs functional responses to ischaemia-reperfusion in rat isolated perfused heart.

1. The effect of acute (50 micromol/L) and chronic (0.06% in drinking water for 14 days) caffeine on the response to ischaemia-reperfusion was studied in Wistar rat isolated perfused hearts. 2. Neither acute nor chronic caffeine modified normoxic heart rate or left ventricular pressures. However, acute caffeine decreased coronary flow by up to 20%, while chronic caffeine consumption increased coronary flow by approximately 15% and abolished the vasoconstrictor effect of acute caffeine (P<0.05). 3. After 15 min global ischaemia, chronic caffeine treatment did not alter the recovery of left ventricular diastolic pressure (LVDP), end-diastolic pressure (EDP) or heart rate during reperfusion, but did enhance coronary flow rate (P<0.05). Acute caffeine inhibited the recovery of LVDP and elevated postischaemic EDP in both caffeine-naive and chronic caffeine-treated groups. Acute caffeine also significantly inhibited coronary reflow in naive but not chronic caffeine-treated groups and produced a transient tachycardia during reperfusion in hearts from chronic caffeine-treated rats. 4. The incidence of arrhythmias was unaltered by chronic caffeine treatment, but was increased by acute caffeine in both naive and chronic caffeine hearts. 5. In conclusion, chronic caffeine intake alone has no detrimental effects on recovery from ischaemia; however, acute caffeine worsens postischaemic contractile function in hearts from naive and chronic caffeine-treated rats.

Age-related changes in adenosine in rat coronary resistance vessels.

1. The vasodilator effects of adenosine receptor agonists, isoprenaline and histamine were examined in perfused heart preparations from young (4-6 weeks) and mature (12-20 weeks) rats. 2. Adenosine induced a biphasic concentration-dependent decrease in KCl (35 mM) raised coronary perfusion pressure in hearts from young and mature rats, suggesting the presence of both high- and low-affinity sites for adenosine receptors in the two age groups tested. In heart preparations from mature rats, vasodilator responses to adenosine were significantly reduced compared with responses observed in young rats. 3. Responses to 5'-N-ethylcarboxamidoadenosine (NECA) and 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680) were reduced in preparations from mature rats, whereas the vasodilator actions of N6-cyclopentyladenosine (CPA) and N6-2-(4-aminophenyl)ethyladenosine (APNEA) did not change with age. 4. The results presented in this study suggest that several adenosine receptor subtypes mediate vasodilator responses in the coronary circulation of the rat and that a reduction in response to adenosine with age may be due to changes in the high-affinity receptor site.

Functional and metabolic effects of extracellular magnesium in normoxic and ischemic myocardium.

Metabolic and functional responses to extracellular Mg2+ concentration ([Mg2+]o) were studied in perfused rat heart. Elevations of [Mg2+]o from 1.2 to 2.4, 5.0, and 8.0 mM dose dependently reduced contractile function and myocardial oxygen consumption (MVO2) up to 80%. Intracellular Mg2+ concentration ([Mg2+]i) remained stable (0.45-0.50 mM) during perfusion with 1.2-5. 0 mM [Mg2+]o but increased to 0.81 +/- 0.14 mM with 8.0 mM [Mg2+]o. Myocardial ATP was unaffected by [Mg2+]o, phosphocreatine (PCr) increased up to 25%, and Pi declined by up to 50%. Free energy of ATP hydrolysis (DeltaGATP) increased from -60 to -64 kJ/mol. Adenosine efflux declined in parallel with changes in MVO2 and [AMP]. At comparable workload and MVO2, the effects of [Mg2+]o on cytosolic free energy were mimicked by reduced extracellular Ca2+ concentration ([Ca2+]o) or Ca2+ antagonism with verapamil. Moreover, functional and energetic effects of [Mg2+]o were reversed by elevated [Ca2+]o. Despite similar reductions in preischemic function and MVO2, metabolic and functional recovery from 30 min of global ischemia was enhanced in hearts treated with 8.0 mM [Mg2+]o vs. 2.0 microM verapamil. It is concluded that 1) 1.2-8.0 mM [Mg2+]o improves myocardial cytosolic free energy indirectly by reducing metabolic rate and Ca2+ entry; 2) [Mg2+]i does not respond rapidly to elevations in [Mg2+]o from 1.2 to 5.0 mM and is uninvolved in acute functional and metabolic responses to [Mg2+]o; 3) adenosine formation in rat heart is indirectly reduced during elevated [Mg2+]o; and 4) 8.0 mM [Mg2+]o provides superior protection during ischemia-reperfusion compared with functionally equipotent Ca2+ channel blockade.

Extracellular adenosine levels and cellular energy metabolism in ischemically preconditioned rat heart.

OBJECTIVE: Microdialysis and 31P-NMR spectroscopy were used to test opposing hypotheses that ischemic preconditioning inhibits adenine nucleotide degradation and purine efflux, or that preconditioning activates cardiovascular adenosine formation to provide enhanced cardioprotection. METHODS: 31P-NMR spectra and matching interstitial fluid (ISF) or venous effluent samples were obtained from Langendorff perfused rat hearts. Control hearts (n = 9) underwent 30 min of global normothermic ischemia and 30 min reperfusion. Preconditioned hearts (n = 6) were subjected to a 5 min ischemic episode and 10 min reflow prior to 30 min ischemia and 30 min reperfusion. Effects of repetitive ischemia-reperfusion (3 x 5 min ischemic episodes) on adenosine levels and energy metabolism were also assessed (n = 8). RESULTS: Preconditioning improved post-ischemic recovery of heart rate x left ventricular developed pressure (71 +/- 5 vs 43 +/- 8%, P < 0.05) and end-diastolic pressure (14 +/- 3 vs 29 +/- 4 mmHg, P < 0.05) compared with control hearts, respectively. Preconditioning did not alter intracellular ATP, phosphocreatine (PCr), inorganic phosphate (Pi), H+ or free Mg2+ during global ischemia, but improved recoveries of PCr, Pi, and delta GATP on reperfusion. ISF adenosine increased more than 20-fold during 30 min ischemia. The 5 min preconditioning episode increased ISF adenosine 3-fold, and reduced ISF adenosine and inosine during subsequent prolonged ischemia by up to 75%. Venous purine levels during reperfusion were also reduced by preconditioning. Accumulation of adenosine in ISF and venous effluent during repetitive ischemia was progressively reduced despite comparable changes in substrate for adenosine formation via 5'-nucleotidase, (5'-AMP), and in allosteric modulators of this enzyme (Mg2+, H+, Pi, ADP, ATP). CONCLUSIONS: (i) Ischemic preconditioning reduces interstitial and vascular adenosine levels during ischemia-reperfusion, (ii) reduced ISF adenosine during ischemia is not due to reduced ischemic depletion of adenine nucleotides in preconditioned rat hearts, (iii) preconditioning may inhibit adenosine formation via 5'-nucleotidase in ischemic rat hearts, and (iv) improved functional recovery with preconditioning is unrelated to metabolic/bioenergetic changes during the ischemic insult, but may be related to improved post-ischemic recovery of [Pi] and delta GATP in this model.

The impact of education and heart attack on smoking cessation among middle-aged adults.

Considerable evidence supports the premise that higher levels of education lead to enhanced health, including protective health behaviors. This paper focuses on how education affects one health behavior known to lead to enhanced health: the cessation of smoking. In particular, the authors examine the extent to which education influences the decision by middle-aged adults to quit smoking following a heart attack, a potentially life-threatening health event. We first hypothesize that middle-aged adults with more formal education will stop smoking more readily than people with less formal education following the experience of a heart attack. Second, we ask what other factors might underlie and explain that hypothesized effect. Using longitudinal data, the authors track changes in individual smoking behaviors after a heart attack among preretirement-age Americans. We control for documented correlates of smoking and heart attack plus other factors associated with education, heart attack, and smoking that may also influence whether a person quits smoking. In addition to confirming evidence on the education-health association as well as the documented connection between heart attack and smoking cessation, this study provides a surprising twist on those links: Our results show that the move to quit smoking following the experience of a heart attack among middle-aged adults is significantly and dramatically moderated by their level of educational attainment.

The partners of welfare mothers: potential earnings and child support.

Public interest in promoting the self-sufficiency of families that depend on welfare concerns the ability of fathers, as well as mothers, to support their children through employment. Many welfare recipients are never-married women, and their children seldom receive child support payments. This article estimates the financial resources that go untapped when child support is not collected from the men who father children who later receive AFDC benefits. While these men may earn little at the time the child is born, their incomes are likely to escalate over time. The child support payments they would make over the child's first 18 years equal almost half of the welfare benefit received by the mother and child. Based on these probable long-term earnings, the authors urge policymakers to invest in efforts to establish paternity and collect child support.

Motives for intergenerational transfers: evidence from Malaysia.

In this paper we discuss a number of hypotheses about motives for intergenerational transfers within the family. We use data on time and money transfers between generations in Malaysia, where there is neither Social Security nor Medicare, to explore these hypotheses empirically. We find evidence supporting the hypotheses that children are an important source of old age security and that old age security is, in part, children's repayment for parental investments in their education. This repayment is partly a function of the children's income and, in the case of females, a function of their spouse's income. We also find evidence supporting the hypotheses that parents and children engage in the exchange of time help for money.

Match quality, new information, and marital dissolution.

"This article investigates the role of surprises in marital dissolution [in the United States]. Surprises consists of changes in the predicted earning capacity of either spouse. Data from the National Longitudinal Study of the High School Class of 1972 is used. We find that an unexpected increase in the husband's earning capacity reduces the divorce hazard, while an unexpected increase in the wife's earning capacity raises the divorce hazard. Couples sort into marriage according to characteristics that are likely to enhance the stability of the marriage. The divorce hazard is initially increasing with the duration of marriage, and the presence of children and high levels of property stabilizes the marriage."

A biphasic response to adenosine in the coronary vasculature of the K(+)-arrested perfused rat heart.

Biphasic vasodilatory responses to adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) were observed in the coronary vasculature of K(+)-arrested perfused rat hearts. Dose-response data for both agonists were best represented by two-site models. For adenosine, two sites with negative log ED50 (pED50) values of 8.1 +/- 0.1 (mean +/- S.E.M) and 5.2 +/- 0.1 were obtained, mediating 31 +/- 2% and 69 +/- 2% of the total response. In the presence of 8-phenyltheophylline, the vasodilatory response to adenosine remained best fitted to a two-site model with pED50 values of 7.0 +/- 0.2 and 5.4 +/- 0.2. The relative contribution of each site to the total response remained unchanged. For NECA, pED50 values of 9.6 +/- 0.1 and 6.8 +/- 0.2 were obtained, representing 48 +/- 3% and 52 +/- 3% of the sites, respectively. In contrast, ATP produced a monophasic response with a pED50 value of 8.8 +/- 0.1. These results provide evidence of adenosine receptor and response heterogeneity in the in situ coronary vasculature.

Novel azole derivatives are antagonists at the inhibitory GABA receptor on the somatic muscle cells of the parasitic nematode Ascaris suum.

The somatic muscle cells of the parasitic nematode Ascaris suum possess GABA receptors that gate chloride conductances in a similar fashion to the mammalian GABAA receptor subtype. These receptors mediate muscle relaxation and are the site of action of the anthelmintic piperazine. The properties of this receptor differ from the properties of the GABA-gated chloride receptors in the mammalian host, in particular they are not as sensitive to mammalian GABA receptor antagonists such as bicuculline and picrotoxin. Using two-electrode intracellular electrophysiological recording techniques from Ascaris muscle cells, we have tested the potency of a series of azole derivatives for their ability to block the chloride-dependent GABA response. The lead compound, SN606078, 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(4,5-dicyano-1H-imidazo l-2-yl)-2H- 1,2,3-triazole, and 4 structurally related compounds reversibly blocked the conductance increase elicited by 30 microM GABA with IC50s of less than 10 microM. SN606078 (10 microM) decreased the slope of the dose-response curve for GABA, suggesting a non-competitive mechanism of action. In two-electrode voltage clamp experiments, 10 microM SN606078 blocked the outward current elicited by 20 microM GABA in a voltage-dependent manner with 72 +/- 2% inhibition at -20 mV and 49 +/- 6% inhibition at -40 mV. These observations indicate that SN606078 may act as an open-channel blocker of the GABA-gated chloride channel in A. suum.

A method to evaluate the response of the coronary circulation of perfused rat heart to adenosine.

Exogenous adenosine causes a monophasic dilation of the coronary vessels in paced, perfused rat heart preparations. Because levels of endogenous adenosine in paced hearts may mask the presence of high potency adenosine receptors, we have developed a method to measure coronary vascular responses in a potassium-arrested heart. Hearts from adult male, Wistar rats were perfused at a constant flow rate of 10 mL/min in the nonrecirculating, Langendorff mode, using Krebs-Henseleit buffer. After 30 min, coronary perfusion pressure was 44 +/- 1 mmHg (mean +/- SEM). Hearts were then perfused with a modified Krebs-Henseleit buffer containing 35 mM potassium. Coronary perfusion pressure increased by 84 +/- 3 mmHg. Adenosine-induced reductions in coronary perfusion pressure were expressed as a percentage of the maximal increase in pressure produced by modified Krebs-Henseleit buffer from the equilibration level. A concentration-response curve for adenosine (n = 6) was biphasic and best described by the presence of two adenosine receptors, with negative log EC50 values of 8.8 +/- 0.3 and 4.3 +/- 0.1, representing 29 +/- 3 and 71 +/- 3%, respectively, of the observed response. Interstitial adenosine sampled by microdialysis during potassium arrest was 25% of the concentration found in paced hearts. Endogenous adenosine in nonarrested hearts may obscure the biphasic response of the coronary vessels to adenosine.

Bound inorganic phosphate and early contractile failure in global ischaemia.

Inorganic phosphate (Pi) accumulates extremely rapidly in ischaemic heart muscle and intracellular binding of this metabolite may account for the precipitous loss of function seen at the onset of severe ischaemia. We have used 31P-NMR spectroscopy to measure the free cytosolic [Pi] and chemical assay techniques to measure total tissue Pi at 0, 1, 2, 3, 4, 5, and 12 min of complete global ischaemia in the isolated isovolumic rat heart. At zero time, the Pi assayed chemically was 30.77 +/- 5.52 mumol/g dry wt (mean +/- SD, n = 7) whilst Pi assayed by NMR was 3.39 +/- 1.21 mumol/g dry wt (n = 15). Thus, 27.38 mumol/g dry wt of Pi was bound at a cytosolic [Pi] of 0.82 mM. After 12 min of ischaemia, 49.88 mumol/g dry wt of Pi was bound at a cytosolic [Pi] of 4.11 mM. When all data were fitted, using a non-linear, least squares fit (p < 0.05), to the binding isotherm: Bound Pi = Bmax'. [Pi]/Kd'+[Pi], the apparent binding parameters Kd' and Bmax' were estimated to be 1.1 +/- 0.6 mM and 64.0 +/- 10.2 mumol/g dry wt respectively. During the first minute of global ischaemia when the rate-pressure product had decreased by 79% of its pre-ischaemic value, bound Pi had increased by 58% and free cytosolic [Pi] by 162%. When functional and metabolite changes were expressed as a fraction of the total change which occurred during the 12-min ischaemic period, bound Pi had the profile most similar to the rate-pressure product. Both the amount of bound Pi and free cytosolic [Pi] correlated with loss of contractile function as the ischaemic period progressed. The results show that during ischaemia, Pi is bound progressively as free cytosolic [Pi] is increased as the result of high energy phosphate hydrolysis. While these results are consistent with the possibility that Pi binding may contribute to ischaemic contractile failure, no molecular explanation for the possible effect of bound Pi on contraction has been proposed.

Chromatin structure and the expression of cardiac genes.

Actively transcribed genes are more susceptible to nuclease digestion, an observation suggested to reflect an altered state of chromatin organization. It has been hypothesized that exposure or sequestration of chromatin domains is a higher order gene regulatory mechanism. In order to test whether tissue lineage is organized by mechanisms at the level or chromatin structure, three cardiac phenotype-conferring genes (atrial natriuretic factor, myosin light chain-1-ventricular and alpha-tropomyosin) have been assessed for DNase 1 sensitivity in nuclei prepared from tissues of the developing guinea pig. These data have been related to the level of tissue mRNA expression of these genes to ascertain whether the exposed state of genes can occur when transcription is low or undetectable. Although this phenomenon was evident in some cases, the data were not consistent with mechanisms at the level of chromatin structure directing tissue type.

Low-density lipoproteins inhibit histamine and NaNO2 relaxations of the coronary vasculature and reduce contractile function in isolated rat hearts.

In the present study we examined the action of native and oxidized low-density lipoproteins (LDL) on coronary vascular and cardiac function and ultrastructure in rat hearts perfused isovolumically in the Langendorff mode. Responses of the coronary resistance vessels to the endothelium-dependent vasodilator, histamine, and the endothelium-independent vasodilator, NaNO2, were measured together with contractile function (rate-pressure product) before and after perfusion for 20 min with native - or oxidized-LDL at a concentration of 100 mu g protein/ml. Ultrastructural damage was assessed via electron microscopy of perfusion-fixed heart specimens. When compared to findings in untreated, control hearts, both native and oxidized LDL significantly reduced the responsiveness of the coronary resistance vessels to histamine and NaNO2, by about 50%. The rate-pressure product was decreased more by oxidized-LDL (41%) than by native-LDL (26%). Electron microscopy showed no ultrastructural abnormalities in the vasculature or myocytes of control hearts. The administration of both native- and oxidized-LDL caused distortion of endothelial cells, increased levels of pinocytotic vesicles in both endothelial and smooth muscle cells, detachment of blood vessels from surrounding tissue, and some regions of myocyte injury with evidence of mitochondrial injury and fluid accumulation. Our results show that both native- and oxidized-LDL are toxic to the isolated heart preparation. They inhibit coronary vascular responsiveness to vasodilators, reduce contractile function, and produce damage to cardiac ultrastructure.

On the ontogeny of cardiac gene transcripts.

As a prerequisite to investigating the specification and differentiation of cardiac tissue in vitro, the ontogeny of a number of putative cardiac-specific, and striated muscle-specific gene transcripts has been studied. The probes used include cDNAs of alpha-actins, myosin heavy chains, myosin light chains, alpha-tropomyosin, troponin-T and atrial natriuretic factor. The expression of these genes was monitored by Northern analysis of heart and various other tissues at three developmental ages, viz, adult, neonatal and mid-foetal. The aim of this exercise was to confirm the efficacy of a number of markers to represent a cardiac-specific subset of gene expression in our mammalian model, the guinea pig. Our results indicate predominantly cardiac expression for the mRNA transcripts of cardiac alpha-actin (c alpha-actin), cardiac myosin heavy chain-alpha (MHC alpha), cardiac myosin heavy chain-beta (MHC beta), myosin light chain-1A (MLC1A), myosin light chain-1V (MLC1V), alpha-tropomyosin (alpha TM), cardiac troponin-T (cTnT) and atrial natriuretic factor (ANF). Furthermore, cardiac-specific expression at the midfoetal time point was observed for five gene transcripts, MLC1V, MHC alpha, MHC beta, striated alpha TM and ANF. No genes were expressed exclusively in cardiac tissue; for example, expression of the genes for c alpha-actin, both cardiac MHCs, both MLCs, alpha TM and cTnT was evident in skeletal and vascular smooth muscles at some stages of development. An interesting difference between this species and those of previous studies was the minor contribution of skeletal alpha-actin to cardiac phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

An algorithm to detect low incidence arrhythmic events in electrocardiographic records from ambulatory patients.

An algorithm was devised to detect low incidence arrhythmic events in electrocardiograms obtained during ambulatory monitoring. The algorithm incorporated baseline correction and R wave detection. The RR interval was used to identify tachycardia, bradycardia, and premature ventricular beats. Only a few beats before and after the arrhythmic event were stored. The software was evaluated on a prototype hardware system which consisted of an Intel 86/30 single board computer with a suitable analog pre-processor and an analog to digital converter. The algorithm was used to determine the incidence and type of arrhythmia in records from an ambulatory electrocardiogram (ECG) database and from a cardiac exercise laboratory. These results were compared to annotations on the records which were assumed to be correct. Standard criteria used previously to evaluate algorithms designed for arrhythmia detection were sensitivity, specificity, and diagnostic accuracy. Sensitivities ranging from 77 to 100%, specificities from 94 to 100%, and diagnostic accuracies from 92 to 100% were obtained on the different data sets. These results compare favourably with published results based on more elaborate algorithms. By circumventing the need to make a continuous record of the ECG, the algorithm could form the basis for a compact monitoring device for the detection of arrhythmic events which are so infrequent that standard 24-h Holter monitoring is insufficient.

Deleterious effects of hydrogen peroxide on the function and ultrastructure of cardiac muscle and the coronary vasculature of perfused rat hearts.

OBJECTIVE: To examine the effect of hydrogen peroxide on the function and ultrastructure of cardiac muscle and the coronary vasculature in an isovolumic rat heart preparation perfused at constant flow. DESIGN: Ventricular function was monitored via a balloon placed in the left ventricle and the response of the coronary vessels to vasodilators was assessed in hearts arrested with 35 mM potassium and treated with 5 microM phenylephrine to contract the coronary resistance vessels. Changes in coronary perfusion pressure reflect changes in resistance vessel tone. SETTING/ANIMALS: This experimental study consisted of 14 heart preparations, six control and eight treated hearts. INTERVENTIONS: Hydrogen peroxide was included in the perfusate at a final concentration of 250 microM for 20 mins. MAIN RESULTS: Hydrogen peroxide reduced rate-pressure product by 42%, caused a fivefold increase in end-diastolic pressure and increased coronary perfusion pressure by 33%. Also, the response of the coronary vasculature to the endothelium-dependent vasodilator, histamine, and endothelium-independent vasodilator, sodium nitrite, was decreased by 55% and 53%, respectively. Electron microscopy of hydrogen peroxide-treated hearts showed damage to both capillaries and arterioles. Endothelial cells were distorted and contained pinocytotic vesicles, endothelial cell junctions were disrupted and blood vessels were detached from surrounding tissue. A comparatively small amount of injury was seen in the myocyte population. CONCLUSIONS: The greater amount of ultrastructural damage seen in blood vessels compared with cardiac muscle suggests that the smooth muscle and endothelial cells of the vasculature are more susceptible to oxidant injury than the myocytes.

Bioenergetics and control of oxygen consumption in the in situ rat heart.

Control of respiration by products of ATP hydrolysis was examined in the in situ rat heart using a purpose-built nuclear magnetic resonance (NMR) coil. The in situ ratio of phosphocreatine to ATP concentrations ([PCr]/[ATP]) was 2.30 +/- 0.05, free Mg2+ concentration ([Mg2+]) was 0.57 mM, and cytosolic pH was 7.35 +/- 0.03 (n = 7). Basal inorganic phosphate concentration ([Pi]) was below NMR detection but was estimated to be 0.83 mM. The [ATP]/[ADP] [Pi] ratio, free ADP concentration ([ADP]), and free energy of ATP hydrolyses (delta GATP) were calculated to be 700,000 +/- 78,000 M-1, 18 +/- 3 microM, and -63.93 +/- 0.33 kJ/mol in situ, respectively (n = 7). In contrast, in the Langendorff perfused rat heart [ATP]/[ADP] [Pi] was only 76,140 +/- 12,830 M-1, [ADP] was 65 +/- 9 microM, and delta GATP was -59.92 +/- 0.48 kJ/mol (n = 7), all indicative of a lower energy state in vitro. Epinephrine infusion in situ (0.9 microgram.min-1.kg-1) increased the rate-pressure product 2.05-fold. During stimulation [ATP] was stable at 97 +/- 3% signal intensity, [PCr] declined by 25%, and [Pi] increased to 1.83 mM. Cytosolic pH was 7.27 +/- 0.01 and [Mg2+] was 0.64 +/- 0.05 mM. [PCr]/[ATP] declined to 1.83 +/- 0.13, and [ATP]/[ADP] [Pi] fell to 108,000 +/- 15,000 M-1. delta GATP only fell marginally to -59.56 +/- 0.49 kJ/mol. Free [ADP] increased threefold to 55 +/- 10 microM. Infusion of 2.8 +/- 0.5 microgram.min-1.kg-1 epinephrine increased the rate-pressure product 2.7-fold, further reduced [ATP]/[ADP] [Pi] (5% of basal), and elevated [ADP] more than fourfold without changing [ATP]. We conclude that the in situ heart is highly energetic compared with isolated perfused hearts and operates at a different metabolic "set-point." Because free [ADP] and [Pi] in situ approximate apparent Michaelis constants for mitochondrial respiration in vitro and increase with increased cardiac work, we conclude that each fulfills the criteria for the kinetic control of O2 consumption in the in situ rat myocardium.